Clinical Trials in Orthopaedics Research. Part I. Cultural and Practical Barriers to Randomized Trials in Orthopaedics∗

Randomized clinical trials are the most rigorous clinical research design. However, trials are expensive, time-consuming, and challenging to design and complete. In May 2009, the Clinical Trials in Orthopaedics Research Symposium, sponsored by the American Academy of Orthopaedic Surgeons (AAOS), the Orthopaedic Research and Education Foundation (OREF), and the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), brought together multiple disciplines to define a randomized clinical trials research agenda by focusing on important clinical questions in each subspecialty and to debate the major important methodological, cultural, and practical barriers to performing more randomized clinical trials in orthopaedics. We defined barriers as any challenge that makes a randomized clinical trial difficult to design or perform. We plan to report the deliberations of the Clinical Trials in Orthopaedics Research Symposium in three publications. The purpose of this first article is to present the cultural and practical barriers and to highlight the key infrastructure needed to support performing randomized trials in orthopaedics. We largely focused on randomized clinical trials but realized that methodologically sound prospective cohort studies also provide important information1. Our deliberations were clearly not exhaustive, and readers can refer to texts for basic information about randomized clinical trials not addressed during the symposium2. We have included the names of symposium speakers in parentheses after the title for each section. Cultural Issues (Marc Swiontkowski and James Wright) Randomized clinical trials have been infrequently performed in surgery3. We use the term culture in this article to reflect how orthopaedic surgeons resolve clinical questions, respond to clinical controversies, express their participation enthusiasm, and respond to the results of randomized clinical trials. Culture is one potential explanation for the paucity of trials in orthopaedics and may be a barrier to more trials. Each surgical procedure provides challenges that require ingenuity and often require deviations from standard practice. Evidence-based medicine, in contrast, proposes a standardized approach that treatment should be based on the best evidence, ideally from randomized trials4. The culture of orthopaedic surgery is one of acceptance and even promotion of divergence in opinions and treatment recommendations. Surgeons also strongly value personal experience. This preference is reflected in the predominant form of clinical research, the case series, which is usually a report of many years of experience. The reliance on experience also explains why surgeons often defer to senior or expert colleagues. However, an uncontrolled case series seldom resolves a clinical question definitively for many reasons, including uncertainty about surgical proficiency, different patient groups, and the effects of cointerventions. Furthermore, there is as much disagreement among experienced or expert clinicians as there is within the surgical literature. When randomized trials are available, surgeons often vigorously defend certain procedures even with evidence of no benefit. Some surgeons perceive randomized trials with suspicion even to the point of viewing trials that challenge the benefit of surgical procedures as an attack on the specialty. The end result is our frequent inability to resolve clinical controversies leading to wide variations in geographic practice patterns5. Given that all of the treatment options probably do not provide equivalent outcomes, patients may not be receiving ideal treatment. If evidence-based medicine and randomized trials are held as an alternative paradigm, it is important to ask, “What is the value of randomized clinical trials?” One particularly cogent example comes from pediatric oncology6. Over the past thirty years, the death rate for pediatric patients with a malignant tumor has decreased substantially. This dramatic improvement in outcome has been attributed almost exclusively to the results from randomized trials. The Clinical Oncology Group, involving thousands of oncologists across North America, has approximately fifty trials ongoing at any one time, with the majority of children in North America with cancer entered into a randomized clinical trial6. The challenge for orthopaedic surgeons is to provide similar leaps in outcome. Why is orthopaedics different from internal medicine or pediatric oncology? Whether through selection or training, surgeons are fiercely independent. Individual surgeons feel compelled to “know” the right answer for every patient. While individual surgeons know the correct answer for them, they acknowledge that other surgeons have a different answer for the same patient. The culture of orthopaedics no doubt begins with residency. The training of surgeons is still largely an apprentice model and highly hierarchical. As role models, surgeons provide little impression of doubt or uncertainty. For good reason, operating rooms leave little room for uncertainty. Furthermore, for surgeons, equipoise—comfort in recommending either of two treatment options—is seen as a sign of weakness in the surgeons’ need to provide and reinforce definitive answers. Patients also want to know the “right” answer. As discussed above, surgeons are slow to accept the results of randomized trials. Surgeons have many explanations for why they reject study results that challenge their views, including “my patients are different,” “the surgeons in the trial don’t have sufficient skill,” “the authors set up the study to get this result,” and “the results don’t reflect my experience.” Residency programs contain little to minimal training in research methods, and few surgeons have specific training in randomized clinical trials. Education in randomized clinical trials during residency is hard to develop because of the primary focus on clinical skills and the additional time required. After surgeons become faculty or clinical practitioners, reimbursement often penalizes those who perform research. While randomized clinical trials are often of high impact, because they usually span a minimum of five years, they often result in only one or two publications and a curriculum vitae that does not fill up quickly. Thus, the low ratio of publications to the time and effort expended may serve as a deterrent. As discussed later, participation in randomized trials involves a different set of frustrations including the exacting requirements of institutional review boards, lack of hospital support, trial costs, less efficiency in providing patient care, and difficulty in enrolling patients. The surgeons with the largest practices are often the most unwilling to join. Rather than struggle through all of the practical requirements of randomized trials, it is easier to do surgery. Culture appears to be both a barrier for orthopaedic surgeons to participate in randomized clinical trials and an influence on how they respond to the results of randomized clinical trials. At the symposium, leadership was proposed as a solution for cultural barriers to the performance of randomized trials. Surgical leaders must admit uncertainty and acknowledge equipoise. Leaders also need to promote research, particularly randomized clinical trials. As such, leaders will influence their peers and, more importantly, the trainees as the next generation of orthopaedic surgeons. Participation in trials takes time. While some may advocate or accept financial penalty, a better model is to change compensation so that leading or participating in randomized trials does not penalize individual surgeon faculty members. While a select few will commit to the necessary training to design randomized trials, an option for most surgeons is to become a team member rather than the principal investigator of a randomized trial. Finally, leaders need to advocate within their specialties. There are many activities within specialty societies that can promote randomized clinical trials, including establishing formal clinical trials committees, providing instructional courses for randomized trial design, and providing for grant funding7. While we have certainly not caught up to pediatric oncology, the number of randomized trials in orthopaedics is on the rise. In The Journal of Bone and Joint Surgery (American Volume), since 1975, the percentage of all published studies that are randomized clinical trials has increased from 4% to 21% and the percentage of case series has decreased from 81% to 48%8. In summary, the culture of orthopaedics is slowly but clearly changing to an evidence-based approach. Training and Experience of the Investigator (Robert Marx) Throughout the symposium, the need for specific training in randomized clinical trials was apparent. The lack of sufficient skill or training in randomized clinical trials may be a barrier because it is difficult to design a randomized clinical trial without MSc and/or MPH or PhD training. The OREF-AAOS Health Service Research fellowship, discontinued for lack of funding, has trained many of the current leaders in orthopaedic clinical research, and this type of training is critical. Research training is difficult to fit into orthopaedic residency, and funding for research training is problematic. Even if a surgeon has research training, conducting a successful randomized trial requires involvement of multiple disciplines with appropriate experience. For those new to running a randomized trial, mentorship, such as including a coinvestigator who has run a trial, is important. Experienced trials personnel, such as research coordinators and data management experts, are invaluable. It is extremely useful for institutions to have infrastructure such as research nurses, and individuals with data management and biostatistical experience. Even with support, execution is time-consuming, enrolling patients is frustrating and slower than expected, and maintaining morale is a constant dilemma. Assembling a sufficient sample size frequently requires the participation of other investigators and/or centers that may not enroll enough patients, do not obtain follow-up for all patients, or deviate from the protocol. At the symposium, we heard that the solution is to have formal training in randomized clinical trials and to include experienced personnel. To address the issues that arise in multicenter trials, regular and/or frequent contact with participating investigators, including providing and reviewing enrollment numbers by center and/or participant, is required. Realistically, running a randomized trial takes a minimum of one to three days per week for the principal investigator. This commitment takes away from clinical time, with possible financial barriers that need to be addressed by leaders. In summary, appropriate expertise and experience are essential to a successful trial. Barriers to Randomized Clinical Trials: An Academic Perspective (Daniel Berry) Institutions and/or departments have several potential barriers to performing randomized clinical trials, including cost, time, surgeon resistance, questionable relevance and/or value, conflicts of interest, and patients. Funding for randomized trials often does not cover the entire costs associated with the trial. While direct costs should include clinical resources, equipment, and costs of research personnel, trial costs may even be greater when no infrastructure exists before the onset of the trial. Randomized trials also involve physician costs, including study administration time to obtain informed consent, and the additional clinical time for study patients. Surgeons have entrenched beliefs that may interfere with trial participation and enrolling patients. New techniques may also serve as a barrier to surgeon participation because of the surgeon’s unfamiliarity and lack of proficiency. Conflict of interest may interfere with surgeon participation because they are involved in the treatment(s) being evaluated or in potential alternative treatment(s) to those evaluated in the randomized trial. Finally, patients come with their own preferences and/or reluctance toward randomization. The solution is to consider potential revenue associated with studies, including the ability to increase business on the basis of reputation or expertise. Randomized clinical trials, particularly those involving new technologies, may serve as a drawing point for doctors and patients. In the design of clinical trials, the logistical aspects should be planned to minimize the burden on the doctor and the hospital. Department chairs have a prominent role in recognizing and promoting the academic value of randomized clinical trials to staff and hospital administration. Department chairs also have a role in focusing clinical researchers on important and feasible clinical questions. Conflict of interest needs to be managed institutionally to maximize surgeon participation. While the preference of patients with regard to treatment choices must be respected, institutions can help patients to understand that randomized clinical trials are a common feature of many academic institutions and that uncertainty about the best treatment is the rationale for a randomized trial. Infrastructural Requirements (Michael Bosse) The larger the randomized trial is, the more complex the required infrastructure—often overwhelming the investigator and serving as a barrier to randomized trial initiation. While not all randomized trials require all aspects of infrastructure shown in Figure 1, all trials require that all tasks be performed. The executive committee, chaired by the principal investigator, oversees the running of the randomized trial, including financing decisions, any issues that arise in each of the sites enrolled in the trial, and interfacing with the data safety monitoring board and the granting agencies. The data coordinating center manages day-to-day operations, including training of staff, maintaining a manual of operations, managing data, monitoring regulatory compliance, maintaining institutional review board approvals, managing budget, and overseeing web sites, if appropriate. The steering committee, comprising all site leads, reviews recruitment and any changes to protocol. The adjudication committee, which must be at arm’s length from the investigators, evaluates individual patient eligibility if uncertain, performs outcome determination when not clear, and identifies protocol violations. Protocol violations in turn must be reported to the institutional review board. The publication committee determines which papers will be written, the potential authorship, and the order of authorship. While decisions on authorship cannot often be finalized until the papers are finished, the earlier the discussion occurs, the less likely there will be disputes and damaged relationships. A database management center, essential for large multicenter studies, determines data elements and monitors the transfer, completeness, and quality of data. Finally, most funding agencies require a data safety monitoring board, which is often constituted by the granting agency and in other cases is formed by the institutional review board. 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